AB0385 BARICITINIB LEADS TO RAPID AND PERSISTENT RESOLUTION OF SYNOVITIS AS MEASURED BY HAND MRI IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (RA) FAILING cs/bDMARD THERAPY
Authors: S. Kemenes, S. Bayat, D. Simon, G. Krönke, D. Bohr, L. Valor, F. Hartmann, L. Schuster, K. Tascilar, G. Schett, A. Kleyer
Journal: Annals of the Rheumatic Diseases (2022)

Background RA is characterized by synovial inflammation resulting in local bone loss [1]. Inhibitors of JAK/Stat pathways, such as baricitinib, demonstrated efficacy in reducing signs and symptoms of RA in clinical trials, however, little is known about their effects on synovitis and bone structure [2]. Preclinical and clinical observations suggest a positive effect JAK inhibitors on bone mass and microstructure, however no prospective, interventional clinical trial has been performed so far [3]. Objectives The aim of this study is to evaluate the effect of baricitinib on local inflammation (synovitis and osteitis) and bone structure (erosions) in RA patients failing on cs/bDMARD therapy using hand MRI. Methods BAREBONE is a prospective, interventional, open label, monocentric single center study (EUDRACT 2018-001164-32 / NCT03701789 ) to assess the effect of baricitinib (4mg/day) on local MRI inflammation and structure in patients with active RA. Besides demographic and clinical characteristics, hand joint inflammation was assessed by magnetic resonance imaging (MRI) using a 1.5 Tesla scanner (Siemens Magnetom Aera T1w TSE cor, T2w TIRM cor, T2w TSE fat-sat trans, T1w TSE fat-sat trans + cor after KM;). at baseline, week 24 and week 48. Scans were assessed for synovitis, osteitis and bone erosions using the RAMRIS scoring system using two independent blinded readers (SK and SB). Intraclass correlation coefficients were calculated for total RAMRIS and synovitis, erosion and osteitis subscores and in a second step differences between cs and bDMARD failure were elaborated. Variables are summarized descriptively using means and 95% bootstrap confidence intervals for continuous outcomes and as number and percentages for categorical outcomes. Results Thirty- two RA patients were screened and 30 patients were included (age: 53.4 [SD 12.6] years; sex: f/m N 24/6; disease duration: 3 [IQR 2.0 – 8.0] years; biologic naïve/bDMARD failure 16/14). 27 patients completed the trial while MRI data was available for 24 patients at week 48. Demographics and clinical characteristics can be seen in Table 1. Total RAMRIS scores slightly decreased from 20.6 (95% CI 14.4 -27.8) at baseline (BL) to 18.3 (11.5 -26.5) at week 48. The synovitis subscore mainly contributed to total RAMRIS reduction by significantly improving from 5.3 (4.0 - 6.8) at BL to 2.7 (1.5 - 4.0) at week 48 with a score change of -2.9 (-4.0 to -1.8). At week 48, 12 patients (44.4%) had no signs of synovitis compared to only 3 patients at BL. In contrast, RAMRIS osteitis subscores only marginally decreased from 4.9 (2.2 - 8.4) at BL to 4.0 (1.9 - 6.7) at week 48. RAMRIS erosion score remained stable over the 48-week observation time. A significant difference in RAMRIS synovitis change for biologic naïve -3.8 (-5.2 to -2.6) vs biologic failure -1.0 (-2.2 to 0.4 could be observed at week 48). With respect to clinical disease activity, DAS 28 score decreased from 4.8 (4.5 – 5.1) at BL to 2.9 (2.5 – 3.3) at week 48. Detailed results can be found in Table 1 and Figure 1. Intraclass coefficient (95%CI) for RAMRIS scoring was high for both readers 0.997 (0.994 to 0.998). Table 1. Demographics, DAS 28 ESR, RAMRIS total score and RAMRIS subset scores at baseline, week 24 and week 48 are shown as well as number of patients with improvement and resolution of synovitis. Baseline Week 24 Week 48 N 30 30 27 Age Mean [SD] 53.5 (12.6) Gender female n [%] 24 (80.0) male n [%] 6 (20.0) Disease duration, years Median (IQR) 3.0 (2.0-8.0) DAS-28 ESR Mean [95%CI] 4.8 (4.5 to 5.1) 3.0 (2.7 to 3.3) 2.7 (2.4 to 3.0) MRI available n [%] 30 (100.0) 28 (93.3) 24 (88.9) RAMRIS total Mean [95%CI] 20.6 (14.4 to 27.6) 18.4 (12.6 to 25.4) 18.3 (11.5 to 26.5) RAMRIS total change Mean [95%CI] 0.0 (0.0 to 0.0) -2.1 (-4.0 to -0.4) -3.9 (-7.2 to -0.5) RAMRIS synovitis Mean [95%CI] 5.3 (3.9 to 6.9) 3.5 (2.2 to 4.9) 2.7 (1.5 to 4.0) RAMRIS synovitis change Mean [95%CI] 0.0 (0.0 to 0.0) -1.8 (-2.5 to -1.0) -2.9 (-4.0 to -1.8) RAMRIS synovitis improved patients n [%] 10 (33.3) 13 (48.1) RAMRIS synovitis resolved patients n [%] 10 (33.3) 12 (44.4) RAMRIS osteitis Mean [95%CI] 4.9 (2.2 to 8.4) 3.7 (1.5 to 6.2) 4.0 (1.9 to 6.7) RAMRIS osteitis change Mean [95%CI] 0.0 (0.0 to 0.0) -0.9 (-3.1 to 1.0) -1.9 (-5.7 to 1.1) RAMRIS osteitis improved patients n [%] 2 (6.7) 4 (14.8) RAMRIS erosion Mean [95%CI] 10.4 (7.3 to 14.6) 11.2 (7.7 to 15.0) 11.6 (7.5 to 16.6) RAMRIS erosion change Mean [95%CI] 0.0 (0.0 to 0.0) 0.6 (0.1 to 1.2) 0.9 (0.0 to 2.1) RAMRIS erosion worsened patients n [%] 2 (6.7) 3 (11.1) Conclusion Our study shows that baricitinib primarily reduces MRI synovitis in RA patients that have previously failed csDMARD and bDMARD therapy and particularly in patients who are biologic naïve. References [1]McInnes, I.B. and G. Schett, The pathogenesis of rheumatoid arthritis. N Engl J Med, 2011. [2]Genovese, M.C., et al., Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med, 2016 [3]Adam, S., et al., JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci Transl Med, 2020. Acknowledgements Lilly Deutschland GmbH funded the Barebone trial Disclosure of Interests Stephan Kemenes: None declared, Sara Bayat: None declared, David Simon Speakers bureau: Lilly Pharma Deutschland GmbH, Janssen, Consultant of: BMS, Pfizer, Sanofi, Abbvie, Janssen, Medac, Novartis, Lilly Deutschland GmbH, GileaBMS, Pfizer, Sanofi, Abbvie, Janssen, Medac, Novartis, Lilly Deutschland GmbH, Gilead, Amgen d, , Grant/research support from: Novartis, Gilead, Abbvie, Lilly, Gerhard Krönke Speakers bureau: GSK, Novartis, Consultant of: GSK, Lilly, Novartis, Janssen, Grant/research support from: Lilly, Novartis, BMS, Janssen, Daniela Bohr: None declared, Larissa Valor: None declared, Fabian Hartmann: None declared, Louis Schuster: None declared, Koray Tascilar Speakers bureau: Gilead speaker, Consultant of: UCB, Lilly, Georg Schett Speakers bureau: Janssen, Abbvie, BMS, Lilly, Novartis, Roche, AMGEN, Gilead, UCB, Consultant of: Lilly, Novartis, Abbvie, Grant/research support from: Chugai, Lilly, Novartis, Arnd Kleyer Speakers bureau: Lilly, Novartis, Abbvie, Consultant of: BMS, Pfizer, Sanofi, Abbvie, Janssen, Medac, Novartis, Lilly Deutschland GmbH, Gilead, Amgen , Grant/research support from: Novartis, Lilly Deutschland GmbH, Gilead